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| Item Type: | Article |
|---|---|
| Title: | CD28 co-stimulus achieves superior CAR T cell effector function against solid tumors than 4-1BB co-stimulus |
| Creators Name: | Textor, A. and Grunewald, L. and Anders, K. and Klaus, A. and Schwiebert, S. and Winkler, A. and Stecklum, M. and Rolff, J. and Henssen, A.G. and Höpken, U.E. and Eggert, A. and Schulte, J.H. and Jensen, M.C. and Blankenstein, T. and Künkele, A. |
| Abstract: | Spacer or co-stimulatory components in chimeric antigen receptor (CAR) design influence CAR T cell effector function. Few preclinical mouse models optimally support CAR candidate pre-selection for clinical development. Here we use a model in which murine CAR T cells can be exploited with human tumor xenografts. This mouse-in-mouse approach avoids limitations caused by species-specific factors crucial for CAR T cell survival, trafficking and function. We compared trafficking, expansion and tumor control for T cells expressing different CAR construct designs targeting two antigens (L1CAM or HER2), structurally identical except for spacer (long or short) or co-stimulatory (4-1BB or CD28) domains to be evaluated. Using monoclonal, murine-derived L1CAM-specific CAR T cells in Rag-/- mice harboring established xenografted tumors from a human neuroblastoma cell line revealed a clear superiority in CAR T cell trafficking using CD28 co-stimulation. L1CAM-targeting short spacer-CD28/ζ CAR T cells expanded the most at the tumor site and induced initial tumor regression. Treating patient-derived neuroblastoma xenografts with human L1CAM-targeting CAR T cells confirmed the superiority of CD28 co-stimulus. CD28 superiority was also demonstrated with HER2-specific CAR T cells (targeting ovarian carcinoma xenografts). Our findings encourage incorporating CD28 signaling into CAR design for adoptive T cell treatment of solid tumors. |
| Keywords: | CAR Design, CAR T Cell Trafficking, Preclinical Mouse Models, Neuroblastoma, Animals, Mice |
| Source: | Cancers |
| ISSN: | 2072-6694 |
| Publisher: | MDPI |
| Volume: | 13 |
| Number: | 5 |
| Page Range: | 1050 |
| Date: | 2 March 2021 |
| Official Publication: | https://doi.org/10.3390/cancers13051050 |
| PubMed: | View item in PubMed |
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